Phenethylaminomethyl-chromanones and- thiochromanones

ABSTRACT

PHENETHYLAMINE DERIVATIVES OF THE FORMULA   PHENYL-CH(-R2)-CH(-R1)-NH-CH2-C&lt;(-CH2-Y-((X)N-1,2-   PHENYLENE)-CO-)   WHEREIN Y IS-CH2-,-O-,-S-OR -SO2-,X IS CL, CH2O OR CH3, N IS 0, 1 OR 2, R1 IS H, CH3 OR CH2OH, AND R2 IS H OR OH AND PHARMACEUTICALLY ACCEPTABLE, ACIDADDITION SALTS THEREOF, ARE USEFUL AS ANTIDEPRESSANTS.

United States Patent Olfice 3,706,764 Patented Dec. 19, 1972 ABSTRACT OFTHE DISCLOSURE Phenethylamine derivatives of the formula wherein Y is CHO-, -S- or SO X is Cl, CH O or CH n is 0, 1 or 2, R is H, CH or CH OH,and R is H or OH and pharmaceutically acceptable, acidaddition saltsthereof, are useful as antidepressants.

This invention relates to novel and therapeutically valuablephenethylamine derivatives.

The novel phenethylamine derivatives of this invention are compounds ofthe formula CH -NH-CHCRU-CHGWQ \Y (I) and pharmaceutically acceptable,acid-addition salts thereof, wherein Y represents 'CH,,-, -O-, -S- or SOn represents 0, 1 or 2, X is Cl, CH O or CH R represents H, CH or CHgOH,and R represents H or OH.

The compounds of Formula I can be produced by the Mannich reaction, thatis, by reacting a compound of the formula wherein X, Y and n are as setforth above, with a compound of the formula wherein R and R are as setforth above, or a salt thereof, such as the hydrochloride, andformaldehyde or a formaldehyde supplying substance such asparaformaldehyde.

The reaction is usually carried out in a solvent generally employed inthe Mannich reaction, such as water, methanol, ethanol or isopropanol,under reflux, for 0.5 to several hours.

The starting compound of Formula III is usually employed as anacid-addition salt, such as the hydrochloride, so that the product (I)is usually obtained in the form of a salt with the same acid. Such saltmay, if necessary, be converted into the free base by conventionalalkali treatment. Further, the free base thus obtained may be convertedinto other acid-addition salts by reaction with various inorganic ororganic acids, such as sulfuric, nitric, maleic, oxalic, fumaric,citric, tartaric, malic acids and the like. However, obviously when astarting compound of Formula III is used in the form of a salt with thedesired acid, the product of Formula I is directly obtained as a salt ofthat acid and need not be treated further.

The compounds of Formula I and their pharmaceutically acceptableacid-addition salts have strong reserpine antagonistic activity asshown, for example, by the following test.

The test for reserpine antagonistic activity was performed essentiallyin accordance with the method described by R. Fielden et al. in Methodin Drug Evaluation, pages 149-157 (North-Holland Publishing Company,Amsterdam, 1966; Editors: P. Mantegazza and F. Piccinini). The resultsof the test are set forth in the following table, wherein RD is thesubcutaneous dose of the test compound which prevents ptosis caused bythe administration of reserpine in 30% of the mice.

Reserpine antagonistic activity Test compound: RD mg./kg. body weight Inthe above table, the test compounds, designated by letters, are asfollows:

The actute toxicities of the above compounds administeredintra'peritoneally to mice are as follows:

Compound: LD mg./kg. A 160-320 In view of various tests, including thosementioned above, the compounds of Formula I and their pharmaceuticallyacceptable, acid-addition salts can be safely administered asantidepressants in the form of a pharmaceutical preparation with asuitable and conventional carrier or adjuvant, administrable orally orby way of injection, without harm to the host.

The pharmaceutical compositions may take any conventional form such astablets, capsules, granules, powders, syrups, injectables and the like.

The following are illustrative examples of formulations to beadministered when compounds of Formula I and their acid-addition saltsare administered for pharmaceutical purposes.

(a) Capsules are prepared from the following composition:

(b) Tablets are prepared from the following composition:

Mg. Compound B 28.1 Lactose 65.0 Starch 26.9

-(c) Powders (10%) are prepared from the following composition:

Compound C 11.2 Lactose 70.0 Starch 18.8

The daily antidepressant dose of compounds of Formula I orpharmaceutically acceptable salts thereof in warm-blooded animals mayusually range from about 0.5 to about 4.0 mg./kg. of body weight. Forexample, the usual daily dose for adult humans for this purpose mayrange from about 50 to 250 milligrams (e.g., about 2 to 10 tablets orcapsules of either formulation (a) or (b), above).

In the following illustrative examples of typical and presenltypreferred embodiments of the invention, g. and ml. represent gram(s) andmilliliter(s), respectively.

EXAMPLE 1 A mixture of 7.4 g. of chroman-4-one, 9.5 g. of norephedrinehydrochloride, g. of paraformaldehyde and ml. of ethanol is refluxed for3 hours. After allowing the mixture to cool overnight, the crystalsprecipitated are collected by filtration and recrystallized from 50%aqueous ethanol to give 5 g. of 3-[N-(2-hydroxy-1-methyl-2-pheny1ethyl)aminomethyl]chroman 4 one hydrochloride melting at 182to 185 C.

EXAMPLE 2 A mixture of 17 g. of amphetamine hydrochloride, 12.6 g. of1,2,3,4-tetrahydronaphthalin-l-one, 10.8 g. of paraformaldehyde and 14ml. of ethanol is refluxed for 3 hours. After cooling, the precipitateis collected by filtration and recrystallized from ethanol to give 25 g.of 2- [N-(l methyl 2 phenylethyl)aminomethyl]-1,2,3,4-tetrahydronaphthalin-l-one hydrochloride melting at 166 to 167 C.

EXAMPLE 4-10 Proceeding by the method of the above examples, butsubstituting equivalent amounts of appropriate starting materials, thefollowing compounds are also produced.

('4) 3-[N-(1-methyl 2 phenylethyl)aminomethyl]- chroman 4 one, itshydrochloride melting at 180 to 183 C.;

(5) 2-[N-(1-methyl 2 phenylethyl)aminomethyl]-7-methoxy-1,2,3,4-tetrahydronaphthalin-l-one, its hydrochloride meltingat 186 C.;

(6) 3-[N-(1-methyl 2 phenylethyl)aminomethylJ- thiochroman-4-one, itshydrochloride melting at 151 to 153 C.;

(7) 2[N-'(Z-hydroxy-l-methyl-Z-phenylethyl)aminomethyl-6-chlorothiochroman 4one, its hydrochloride melting at 162 to 164 C.;

(8) 2 [N-(Z-hydroxy-1-methyl-2-phenylethyl)aminomethyl]-6,7-dimethyl1,2,3,4 tetrahydronaphthalin-lone, its hydrochloride melting at C.;

(9) 2 [N-(Z-hydroxy-l-methyl-Z-phenylethyl)aminomethyl] -7-methoxy1,2,3,4 tetrahydronaphthalin-l-one, its hydrochloride melting at 175 C.and shown [111 +51.5 (c.=0.02, methanol).

(10) 2-[N-(2 hydroxy 1 methyl-2-phenylethyl)-aminomethyl]thiochroman-4-one 1,1-dioxide, its hydrochloride melting at245 to 246 C.

What is claimed is:

l. A compound selected from the group consisting of phenethylaminederivatives of the formula:

wherein Y is a member selected from the group consisting of -0-, '-S-and SO;; n represents an integer of 0, 1, or 2; X represents a memberselected from the group consisting of Cl, CH O and CH R is a memberselected from the group consisting of H, CH and (DH- 0H; and R is amember selected from the group consisting of H and OH, and thepharmaceutically acceptable, acid-addition salts thereof.

2. A compound of claim 1 having the name 3-[N-(2- hydroxy-l-methyl 2phenylethyl)aminomethyl]chroman-'4-one.

3. A compound of claim 1 having the name 3-[N-(lmethyl-2-phenylethyl)aminomethyl] chroman-4-onc.

4. A compound of claim 1 having the name3-[N-(lmethyl-2-phenylethyl)-aminomethyl]thiochroman-4-one.

5. A compound of claim 1 having the name 6-chloro- Z-[N-(Z-hydroxy 1methyl 2 phenylethyl)aminomethyl]thiochroman-4-one.

6. A compound of claim 1 having the name 2-[N-(2- hydroxy 1 methyl 2phenylethyl)aminomethyl]thiochroman-4-one 1,1-dioxide.

, References Cited Chu, et al., C. A. 52211044 (8-58). Kaushiva, Ann.Biochem. Exptl. Med. (Calcutta), Suppl. 20, pp. 493-504 (1960).

HEN-RY R. JILES, Primary Examiner C. M. S. JAISLE, Assistant ExaminerUS. Cl. X.R.

